In this application for the Pharmacogenomics of Anticancer Agents Research in Children (PAAR4Kicls), the goal is to fully define the pharmacogenomics of childhood acute lymphoblastic leukemia (ALL), the most common childhood malignancy, in order to improve the lives of children with this disease, as well as any patients treated with the same medications. Our aims are to define genomic variations (germline and acquired) important for interpatient variability in treatment response and toxicity from medications used to treat childhood ALL, to translate pharmacogenomics into clinical treatment strategies, and to collaborate with pharmacogenomics investigators to leverage relevant pharmacogenomic knowledge from pediatric ALL to other diseases and disciplines (and wee-versa). This is accomplished by a multidisciplinary team of leaders in the field. The research harnesses the power of studying patients with ALL treated on Children's Oncology Group (COG) and St. Jude Children's Research Hospital protocols, achieving near-population-level coverage for ALL in the US. Pediatric ALL provides outstanding opportunities for pharmacogenomic discoveries and translation to the clinic, because this is an otherwise fatal disease that is cured through extensive use of agents that have a narrow therapeutic index. The agents are broadly used in cancer and in general medical practice and thus the findings from PAAR4Kids have applicability outside of pediatric ALL, as demonstrated by multiple collaborations within and outside of the PGRN. PAAR4Kids studies the pharmacogenomics, pharmacokinetics (cellular and plasma), antileukemic and toxic effects of glucocorticoids, methotrexate, thiopurines, asparaginase, anthracyclines, and vincristine. The approach is summarized in four major Steps. In Step 1 genotype/phenotype studies are undertaken in a set of core phase III front-line clinical trials involving over 10,000 patients that serve as discovery and replication cohorts. Non-genetic covariates are included. In Step 2, genomic variation is prioritized for further follow-up. Step 3 is confirmation and validation, consisting of mechanistic experimental laboratory models, surveys of human tissues, and/or additional genotype/phenotype analyses in other clinical trials, often using PGRN resources. In Step 4, validated genomic associations with large effect sizes are integrated into clinical settings. PAAR4Kids has world class scientists applying state-of-the-art genomics techniques to the germline and tumor cells of impeccably cataloged specimen collections from extensively phenotyped patients, and outstanding statisticians, pharmacologists, and clinicians. PAAR4Kids is poised to comprehensively attack the pharmacogenomics of childhood ALL.